Innate immunomechanism plays a key role in a first defense against pathogen infection, and recognition and recovery of damaged tissue and is mediated by certain cells such as a macrophage and a dendritic cell, and humoral factors such as a complement system and a clotting system.
Particularly, inflammatory response of the innate immune system is a in vivo defense mechanism caused by bacterial endotoxins and tissue damages, and is accompanied by the increase of inflammatory cells (macrophages, dendritic cells, etc.) and proinflammatory cytokines (interleukine-12, TNF-α, etc.), fervescence, local effusion of tissue fluid, fibroplasia for recovery, etc. The activation of such proinflammatory cells can be confirmed by the proinflammatory cytokine production as well as the expression of nuclear transcription factors which are involved in the regulation of the transcription of inflammatory cell genes, and the expression of co-stimulating molecules (CD40, CD80, CD86) or major histocompatibility complexes (MHCs) which are involved in the activation of the inflammatory cells.
Also, the inflammatory cells including antigen presenting cells (APCs) in the innate immunomechanism induces directly or indirectly the activation of the acquired immunomechanism induced by T-cells and B-cells. The acquired immune response activated by systemic inflammatory response exacerbates inflammatory response as well.
Toxin (endotoxin of exotoxin) is an example of a material which can induce an abnormal activation of the innate immune system and an inflammatory response. Endotoxin such as glycolipid of E. coli is an amphiphilic molecule which has both hydrophilic regions and hydrophobic regions such as lipid region, and is a principal material constituting a cell wall of Gram-negative bacteria.
Particularly, it is known that the lipid region of the endotoxin has a strong hydrophobicity and plays an important role in the induction of the cytotoxicity. Therefore, various diseases and conditions are induced by the endotoxin. Sepsis, in particular, can cause serious problems in an emergency room or during an operation.
Sepsis induces a serious inflammation in bloods and various organs as bacterial toxins circulate through blood vessels. Sepsis also causes a variety of symptoms such as pyrexia, vomiting, diarrhea, blood pressure drop, tachypnea, tachycardia, frequent urination, stupor, etc.
Sepsis is the third major cause of death in the developed countries. More than 750,000 people are affected by sepsis annually in the United States, and 9% of total deaths in US die from sepsis.
Exotoxin excreted by Gram-positive or Gram-negative bacteria can also induce an inflammation. The exotoxin is comprised of proteins, and is produced and excreted during the metabolic process of Corynebacterium diphteriae, Clostridium tetani, Clostridium botulinum, etc. Similar exotoxins are produced by dysentery bacillus, streptococcus, etc.
Inflammatory responses through an abnormal innate immunoactivity are rising as important problems in an organ transplatation, and one of the problems is the immunorejection which occurs during transplanting porcine cells to a human. Such immunorejections are activated by tissues damaged during an operation as well as natural antibodies existing in blood, and cause tissue necrosis with a serious inflammatory response.
In particular, organ damages due to ischemic anoxia during the extirpation of an organ from a donor, damage during the preservation of an organ before transplantation, and formation of active oxygen and increase in immune responses after reperfusion, have been rising as an important problem.
Therefore, an organ preservative solution which can minimize damages of the organ to be transplanted and immunorejections, is required. Currently, various commercial organ preservative solutions, for example the University of Wisconsin solution developed by the University of Wisconsin in USA and HTK (Histidine-Tryptophan-Ketoglutarate) solution developed in Germany are available. The organ preservative solution is injected as a perfusate before the extirpation of an organ from a donor, or is used for the preservation of an organ before the transplantation of the organ to a patient. However, the conventional organ preservative solutions have limitations on the suppression of inflammatory responses induced by the organ damaged during the transplantation.
Like this, it is important for various inflammatory diseases as well as an organ transplantation to control inflammatory responses.
The conventional anti-inflammatory agents and immunosuppressive agents having an inflammatory suppression effect have disadvantages that the agents have a topical effect and are required for a continuous administration. The agents also have adverse effects when administering the agents.
Vioxx®, a nonsteroidal anti-inflammatory drug (NSAID), is used for the treatment of arthritis, and however it is reported that Vioxx® increases twice the morbidity of heart disease, according to clinical trials. Consequently, the safety of other drugs having an inflammation inhibition mechanism similar to that of Vioxx® is under investigation.
Steroidal anti-inflammatory drugs also have adverse effects. When these steroidal anti-inflammatory drugs are abused, in vivo disease resistance decreases, and therefore the human body becomes sensitive to take diseases such as diabetes, osteoporosis, etc.
Xigris®, the first commercialized therapeutic agent for sepsis, intervenes in the blood clotting process, and therefore can cause a severe bleeding or apoplexy.
U.S. Pat. Nos. 5,283,236 and 5,658,878 disclose sodium glycocholate and derivatives thereof. However, the above patents disclose a use of sodium glycocholate only as a drug delivery enhancing agent, not as an anti-inflammatory agent.
In addition, M. Katsrma et al. reported, in their study of the enhancement of drug delivery ability in colon, that the colonic absorption of insulin is enhanced when sodium glycocholate or polyethylene oxide is administered together with insulin (International Journal of Pharmaceutics, 2006, pp. 156-162). However, Katsrma et al. do not also disclose the anti-inflammatory effect of sodium glycocholate and derivatives thereof.
Therefore, it has been keenly required for the development of a novel drug which can complement defects of the conventional anti-inflammatory agents and enhance the therapeutic effect of an anti-inflammatory agent on inflammation.